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Background Cerebrospinal fluid (CSF) p-tau235 is a novel biomarker highly specific of Alzheimer’s disease (AD). However, CSF p-tau235 has only been studied in well-characterized research cohorts, which do not fully reflect the patient landscape found in clinical settings. Therefore, in this multicentre study, we investigated the performance of CSF p-tau235 to detect symptomatic AD in clinical settings and compared it with CSF p-tau181, p-tau217 and p-tau231. Methods CSF p-tau235 was measured using an in-house single molecule array (Simoa) assay in two independent memory clinic cohorts: Paris cohort (Lariboisière Fernand-Widal University Hospital Paris, France; n=212) and BIODEGMAR cohort (Hospital del Mar, Barcelona, Spain; n=175). Patients were classified by the syndromic diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI] or dementia) and their biological diagnosis (amyloid-beta [Aβ]+ or Aβ $$-$$ - ). Both cohorts included detailed cognitive assessments and CSF biomarker measurements (clinically validated core AD biomarkers [Lumipulse CSF Aβ1–42/40 ratio, p-tau181 and t-tau] and in-house developed Simoa CSF p-tau181, p-tau217 and p-tau231). Results High CSF p-tau235 levels were strongly associated with CSF amyloidosis regardless of the clinical diagnosis, being significantly increased in MCI Aβ+ and dementia Aβ+ when compared with all other Aβ− groups (Paris cohort: P ˂0.0001 for all; BIODEGMAR cohort: P ˂0.05 for all). CSF p-tau235 was pronouncedly increased in the A+T+ profile group compared with A−T− and A+T− groups (P ˂0.0001 for all). Moreover, CSF p-tau235 demonstrated high diagnostic accuracies identifying CSF amyloidosis in symptomatic cases (AUCs=0.86 to 0.96) and discriminating AT groups (AUCs=0.79 to 0.98). Overall, CSF p-tau235 showed similar performances to CSF p-tau181 and CSF p-tau231 when discriminating CSF amyloidosis in various scenarios, but lower than CSF p-tau217. Finally, CSF p-tau235 associated with global cognition and memory domain in both cohorts. Conclusions CSF p-tau235 was increased with the presence of CSF amyloidosis in two independent memory clinic cohorts. CSF p-tau235 accurately identified AD in both MCI and dementia patients. Overall, the diagnostic performance of CSF p-tau235 was comparable to that of other CSF p-tau measurements, indicating its suitability to support a biomarker-based AD diagnosis in clinical settings.

Amyloid (Aβ) pathology is the earliest detectable pathophysiological event along the Alzheimer's continuum, which can be measured both in the cerebrospinal fluid (CSF) and by Positron Emission Tomography (PET). Yet, these biomarkers identify two distinct Aβ pools, reflecting the clearance of soluble Aβ as opposed to the presence of Aβ fibrils in the brain. An open question is whether risk factors known to increase Alzheimer's' disease (AD) prevalence may promote an imbalance between soluble and deposited Aβ. Unveiling such interactions shall aid our understanding of the biological pathways underlying Aβ deposition and foster the design of effective prevention strategies. We assessed the impact of three major AD risk factors, such as age, APOE-ε4 and female sex, on the association between CSF and PET Aβ, in two independent samples of non-demented individuals (ALFA: n = 320, ADNI: n = 682). We tested our hypotheses both in candidate regions of interest and in the whole brain using voxel-wise non-parametric permutations. All of the assessed risk factors induced a higher Aβ deposition for any given level of CSF Aβ42/40, although in distinct cerebral topologies. While age and sex mapped onto neocortical areas, the effect of APOE-ε4 was prominent in the medial temporal lobe, which represents a target of early tau deposition. Further, we found that the effects of age and APOE-ε4 was stronger in women than in men. Our data indicate that specific AD risk factors affect the spatial patterns of cerebral Aβ aggregation, with APOE-ε4 possibly facilitating a co-localization between Aβ and tau along the disease continuum. The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004 and the Alzheimer’s Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017-SGR-892. JDG is supported by the Spanish Ministry of Science and Innovation (RYC-2013-13054). MSC receives funding from Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva programme grant IJC2018-037478-I). KB holds the Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences, and is supported by the Swedish Research Council (#2017-00915); the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243); and a grant (#ALFGBG-715986) from the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL.

Additional file 1. Supplementary methods, tables, and figures.

Additional file 1: Supplementary Figure 1. CSF levels of p-tau235 across clinical diagnosis. Supplementary Figure 2. CSF levels of p-tau235 in Aβ+ and Aβ- cases. Supplementary Figure 3. CSF p-tau235 diagnostic performance discriminating Aβ+ from Aβ- cases. Supplementary Table 1. Clinical diagnosis included in each syndrome group in Paris cohort. Supplementary Table 2. Clinical diagnosis included in each syndrome group in BIODEGMAR cohort. Supplementary Table 3. CSF AD biomarkers cut-offs for BIODEGMAR and Paris Cohort. Supplementary Table 4. Accuracies of CSF p-tau181, p-tau217, p-tau231 and p-tau235 when identifying CSF amyloidosis in dementia and MCI cases in Paris and BIODEGMAR cohort. Supplementary Table 5. Clinical diagnosis included in each AT group in Paris cohort. Supplementary Table 6. Clinical diagnosis included in each AT group in BIODEGMAR cohort. Supplementary Table 7. Accuracies of CSF p-tau181, p-tau217, p-tau231 and p-tau235 when discriminating AT groups in Paris and BIODEGMAR cohort. Supplementary Table 8. Accuracies of CSF p-tau181, p-tau217, p-tau231 and p-tau235 when discriminating Aβ- from Aβ+ in Paris and BIODEGMAR cohort.

Introduction: Harboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described. Methods: Multicenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3). Results: Carrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging. Discussion: In addition to the known resistance against amyloid-β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD-related cognitive decline. The project leading to this study has received funding from “la Caixa” Foundation (ID 100010434), under the agreement LCF/PR/GN17/50300004. Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant number 2017-SGR-892. EMAU is supported by the Spanish Ministry of Science, Innovation and Universities–Spanish State Research Agency (RYC2018-026053-I).

Additional file 1: Table S1. Selected questions from the online ad-hoc questionnaire on worries and lifestyle changes during the COVID-19 confinement.

Key Points Question What are the levels of plasma glial fibrillary acidic protein (GFAP) throughout the Alzheimer disease (AD) continuum, and how do they compare with the levels of cerebrospinal fluid (CSF) GFAP? Findings In this cross-sectional study, plasma GFAP levels were elevated in the preclinical and symptomatic stages of AD, with levels higher than those of CSF GFAP. Plasma GFAP had a higher accuracy than CSF GFAP to discriminate between amyloid-β (Aβ)–positive and Aβ-negative individuals, also at the preclinical stage. Meaning This study suggests that plasma GFAP is a sensitive biomarker that significantly outperforms CSF GFAP in indicating Aβ pathology in the early stages of AD., Importance Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP. Objective To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP. Design, Setting, and Participants This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer’s and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisière cohort (Paris, France), which included individuals with symptomatic AD. Main Outcomes and Measures Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-β 42/40 (Aβ42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD. Results A total of 300 TRIAD participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ participants (234 women [60.9%]; mean [SD] age, 61.1 [4.7] years), and 187 BioCogBank Paris Lariboisière participants (116 women [62.0%]; mean [SD] age, 69.9 [9.2] years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) Aβ-negative individuals (TRIAD: Aβ-negative mean [SD], 185.1 [93.5] pg/mL, Aβ-positive mean [SD], 285.0 [142.6] pg/mL; ALFA+: Aβ-negative mean [SD], 121.9 [42.4] pg/mL, Aβ-positive mean [SD], 169.9 [78.5] pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU Aβ-positive mean [SD], 285.0 [142.6] pg/mL, mild cognitive impairment [MCI] Aβ-positive mean [SD], 332.5 [153.6] pg/mL; AD mean [SD], 388.1 [152.8] pg/mL vs CU Aβ-negative mean [SD], 185.1 [93.5] pg/mL; Paris: MCI Aβ-positive, mean [SD], 368.6 [158.5] pg/mL; AD dementia, mean [SD], 376.4 [179.6] pg/mL vs CU Aβ-negative mean [SD], 161.2 [67.1] pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated Aβ-positive from Aβ-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant Aβ pathology. Conclusions and Relevance This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aβ pathology even among individuals in the early stages of AD., This cross-sectional cohort study evaluates plasma glial fibrillary acidic protein levels throughout the entire Alzheimer disease continuum, from preclinical Alzheimer disease to Alzheimer disease dementia, compared with cerebrospinal fluid glial fibrillary acidic protein.

Alzheimer’s Disease Neuroimaging Initiative., [Importance] Plasma phosphorylated tau at threonine 181 (p-tau181) has been proposed as an easily accessible biomarker for the detection of Alzheimer disease (AD) pathology, but its ability to monitor disease progression in AD remains unclear., [Objective] To study the potential of longitudinal plasma p-tau181 measures for assessing neurodegeneration progression and cognitive decline in AD in comparison to plasma neurofilament light chain (NfL), a disease-nonspecific marker of neuronal injury., [Design, Setting, and Participants] This longitudinal cohort study included data from the Alzheimer’s Disease Neuroimaging Initiative from February 1, 2007, to June 6, 2016. Follow-up blood sampling was performed for up to 8 years. Plasma p-tau181 measurements were performed in 2020. This was a multicentric observational study of 1113 participants, including cognitively unimpaired participants as well as patients with cognitive impairment (mild cognitive impairment and AD dementia). Participants were eligible for inclusion if they had available plasma p-tau181 and NfL measurements and at least 1 fluorine-18–labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) or structural magnetic resonance imaging scan performed at the same study visit. Exclusion criteria included any significant neurologic disorder other than suspected AD; presence of infection, infarction, or multiple lacunes as detected by magnetic resonance imaging; and any significant systemic condition that could lead to difficulty complying with the protocol., [Exposures] Plasma p-tau181 and NfL measured with single-molecule array technology., [Main Outcomes and Measures] Longitudinal imaging markers of neurodegeneration (FDG PET and structural magnetic resonance imaging) and cognitive test scores (Preclinical Alzheimer Cognitive Composite and Alzheimer Disease Assessment Scale–Cognitive Subscale with 13 tasks). Data were analyzed from June 20 to August 15, 2020., [Results] Of the 1113 participants (mean [SD] age, 74.0 [7.6] years; 600 men [53.9%]; 992 non-Hispanic White participants [89.1%]), a total of 378 individuals (34.0%) were cognitively unimpaired (CU) and 735 participants (66.0%) were cognitively impaired (CImp). Of the CImp group, 537 (73.1%) had mild cognitive impairment, and 198 (26.9%) had AD dementia. Longitudinal changes of plasma p-tau181 were associated with cognitive decline (CU: r = –0.24, P, [Conclusions and Relevance] Study findings suggest that plasma p-tau181 was an accessible and scalable marker for predicting and monitoring neurodegeneration and cognitive decline and was, unlike plasma NfL, AD specific. The study findings suggest implications for the use of plasma biomarkers as measures to monitor AD progression in clinical practice and treatment trials., This work was supported by the “Miguel Servet” program grant CP19/00031 of the Spanish Instituto de Salud Carlos III (Dr Grothe); research fellowship A202f0812F from the Brightfocus Foundation, grant AF-930627 from the Swedish Alzheimer Foundation, grant FO2020-0240 from the Swedish Brain Foundation, grant 2020-00124 from the Agneta Prytz-Folkes & Gösta Folkes Foundation, and support from the Swedish Dementia Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Anna Lisa and Brother Björnsson’s Foundation, Gamla Tjänarinnor, and the Gun and Bertil Stohnes Foundation (Dr Karikari); the Paulo Foundation and the Orion Research Foundation (Dr Snellman); grant 752310 from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie action grant agreement, grant PI19/00155 from the Instituto de Salud Carlos III, and grant IJC2018-037478-I from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme) (Dr Suárez-Calvet); grant 2018-02532 from the Swedish Research Council, 681712 from the European Research Council, ALFGBG-720931 from the Swedish State Support for Clinical Research, 201809-2016862 from the Alzheimer Drug Discovery Foundation USA, and the UK Dementia Research Institute at University College London (Dr Zetterberg); grant 2017-00915 from the Swedish Research Council, RDAPB-201809-2016615 from the Alzheimer Drug Discovery Foundation USA, AF-742881 from the Swedish Alzheimer Foundation, FO2017-0243 from Hjärnfonden, Sweden, the Swedish state under the agreement between the Swedish government and the County Councils, ALFGBG-715986 from the ALF-agreement, and JPND2019-466-236 from the European Union Joint Program for Neurodegenerative Disorders (Dr Blennow); KAW 2014.0363 from the Knut and Alice Wallenberg Foundation (Wallenberg Centre for Molecular and Translational Medicine, 2017-02869 from the Swedish Research Council, ALFGBG-813971 from the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement, and AF-740191 from the Swedish Alzheimer Foundation (Dr. Schöll). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (grant AG024904) and Department of Defense ADNI (grant W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc; Cogstate; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co, Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California.

Additional file 1: Figure S1. Association models between Alzheimer’s Disease CSF biomarkers and enlargement of Perivascular Spaces.

Additional file 1: Table S1. Confusion table of group prevalence for each low burden definition. Table S2. CSF biomarker levels by Aβ group including CSF biomarkers extreme values. Table S3. Structural MRI measurements by Aβ group. Table S4. FDG PET measurements by Aβ group. Fig. S1. Comparison of all CSF biomarkers between Aβ groups.

Additional file 1.

Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55–0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19–0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27–0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60–80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.

Background Mounting evidence links poor sleep quality with a higher risk of late-life dementia. However, the structural and cognitive correlates of insomnia are still not well understood. The study aims were to characterize the cognitive performance and brain structural pattern of cognitively unimpaired adults at increased risk for Alzheimer’s disease (AD) with insomnia. Methods This cross-sectional study included 1683 cognitively unimpaired middle/late-middle-aged adults from the ALFA (ALzheimer and FAmilies) study who underwent neuropsychological assessment, T1-weighted structural imaging (n = 366), and diffusion-weighted imaging (n = 334). The World Health Organization’s World Mental Health Survey Initiative version of the Composite International Diagnostic Interview was used to define the presence or absence of insomnia. Multivariable regression models were used to evaluate differences in cognitive performance between individuals with and without insomnia, as well as potential interactions between insomnia and the APOE genotype. Voxel-based morphometry and tract-based spatial statistics were used to assess between-group differences and potential interactions between insomnia and the APOE genotype in gray matter volume and white matter diffusion metrics. Results Insomnia was reported by 615 out of 1683 participants (36.5%), including 137 out of 366 (37.4%) with T1-weighted structural imaging available and 119 out of 334 (35.6%) with diffusion-weighted imaging. Individuals with insomnia (n = 615) performed worse in executive function tests than non-insomniacs and displayed lower gray matter volume in left orbitofrontal and right middle temporal cortex, bilateral precuneus, posterior cingulate cortex and thalamus, higher gray matter volume in the left caudate nucleus, and widespread reduction of mean and axial diffusivity in right hemisphere white matter tracts. Insomnia interacted with the APOE genotype, with APOE-ε4 carriers displaying lower gray matter volumes when insomnia was present, but higher volumes when insomnia was not present, in several gray matter regions, including the left angular gyrus, the bilateral superior frontal gyri, the thalami, and the right hippocampus. Conclusions Insomnia in cognitively unimpaired adults at increased risk for AD is associated to poorer performance in some executive functions and volume changes in cortical and subcortical gray matter, including key areas involved in Alzheimer’s disease, as well as decreased white matter diffusivity.

Additional file 1: Figure S1. Interaction between APOE status and insomnia in cognitive performance. Figure S2. Effect of insomnia on gray matter volume (additionally adjusted by hypertension, dyslipidemia and physical activity). Figure S3. Effect of insomnia on white matter microstructure (additionally adjusted by hypertension, dyslipidemia and physical activity). Table S1. VBM results of the main effect of insomnia, additionally adjusted by hypertension, dyslipidemia and physical activity (puncorrected

Supplementary data including supplementary methods and results. (DOCX 1010 kb)

Figure S1. Description of global and regional WMH burden. Figure S2. Cross-correlation between CAIDE-I percentage of dementia and its individual risk factors. Figure S3. Regional patterns of WMH associations with hypertension measured by different classifications. Table S1. Risk factors taken into account to derive CAIDE dementia risk scores and their corresponding points assigned. Table S2. Associations between global WMH and individual conditions to assess hypertension. Table S3. Comparison of CAIDE risk factors between hypertensive and nonhypertensive participants. Table S4. Comparison of CAIDE risk factors between nonhypercholesterolemic and hypercholesterolemic participants. Table S5. Comparison of CAIDE risk factors between women and men. Table S6. Comparison of CAIDE risk factors between physically inactive and active participants. Table S7. Comparison of CAIDE risk factors between APOE-ε2 carriers and APOE-ε3 homozygotes. Table S8. Comparison of CAIDE risk factors between participants with maternal family history and no family history of AD. (DOCX 1802 kb)

Table S1. Sociodemographic, genetic, and mood descriptive data in the MRI sample. Table S2. Frequency of co-occurrence of SCDplus features in subjects with SCD in the whole sample (n = 572). Table S3. Frequency of co-occurrence of SCDplus features in subjects with SCD in the MRI subsample (n = 109). Table S4. Brain regions showing statistically significant negative associations between the number of SCDplus features met and GM volume. Figure S1. Frequency of SCD subjects by number of criteria met in the whole sample. Figure S2. Frequency of SCD subjects by number of criteria met in the MRI subsample. Figure S3. Brain regions showing a negative linear relation between number of SCDplus features met and GM volume in SCD subjects. (DOCX 441 kb)

La present tesi té com a objectiu estudiar des de diferents punts de vista la degeneració lobular frontotemporal (FTLD), una malaltia neurodegenerativa que es caracteritza per la pèrdua neuronal focal en els lòbuls frontals i temporals. Aquesta malaltia és molt heterogènia des del punt de vista clínic, neuropatològic i genètic, com també en els mecanismes patogènics. Aquesta heterogeneïtat fa que sovint el diagnòstic no sigui fàcil i que la seva classificació nosològica i la recerca en els seus mecanismes sigui especialment complexa. En aquesta tesi s’aborda aquesta heterogeneïtat estudiant diferents aspectes de la FTLD. Primer, s’estudia la FTLD des de un punt de vista clínic: s’avaluen els nous criteris de la variant conductual d’aquesta malaltia (bvFTD) en la cohort de pacients seguits a la Unitat de Memòria de l'hospital de la Santa Creu i Sant Pau. Des del punt de vista genètic, es caracteritzen aspectes clínics i radiològics específics dels casos de FTLD que presenten una expansió de la repetició d’hexanucleòtids en el gen C9orf72. Seguidament, des del punt de vista dels biomarcadors, es mesura en sang i líquid cefaloraquidi la proteïna TDP-43 i la seva forma fosforilada (pTDP-43). En l’últim capítol, s’aprofundeix en els mecanismes moleculars de la patogènia de la FTLD amb dipòsits de proteïnes FUS i FET (FTLD-FET), s’estudien la metilació en les arginines presents en aquests proteïnes i com aquest canvi postraduccional regula el transport citoplasma-nucli de la proteïna FUS. Finalment, es realitza un estudi neuropatològic a on es comparen les diferències en el patró de metilació de la proteïna FUS entre la FTLD-FET i la esclerosi lateral amiotròfica amb mutacions en el gen de FUS (ALS-FUS). Aquest estudi afegeix una nova diferència entre la FTLD-FET i la ALS-FUS, tot i que ambdues comparteixen els dipòsits de la proteïna FUS., The aim of the present thesis is to study frontotemporal lobar degeneration (FTLD), a neurodegenerative disease characterised by a focal neural loss in the frontal and the temporal lobes, from different perspectives. FTLD is a very heterogeneous disease either from the clinical or the neuropathological, genetic and pathogenic perspectives. This heterogeneity makes its diagnosis challenging and its nosologic classification and pathogenesis research especially puzzling. In the present thesis, this heterogeneity is addressed through studying FTLD from different angles. First, FTLD is investigated from a clinical viewpoint: the most recent clinical criteria about the behavioural variant of FTLD (bvFTD) are evaluated through the cohort of patients followed in the Memory Unit of Hospital de la Santa Creu i Sant Pau. From a genetic perspective, specific clinical and radiological features of the FTLD patients carrying a hexanucleotide repeat expansion in the C9orf72 gene are defined. Next, and from a biomarkers angle, TDP-43 protein and its phosphorylated form (pTDP-43) are measured in blood and in cerebrospinal fluid (CSF). In the last chapter, the molecular pathogenic mechanisms of FTLD with FUS- and FET-positive inclusions (FTLD-FET) are scrutinized, in order to study the methylation pattern of the arginines present in FUS protein and how this posttranslational modification regulates the cytoplasmic-nuclear transport. Finally, a neuropathological study is performed by means of the comparison of the differences in FUS methylation pattern between FTLD-FET and amyotrophic lateral sclerosis with FUS mutations (ALS-FUS). This study provides further evidence of the differences between FTLD-FET and ALS-FUS, despite the fact that both diseases share the deposition of the protein FUS.

CSF sTREM2 measurement. Figure S1. Effects of rare TREM2 variants on antibody affinities. Figure S2. CSF sTREM2 in the A/T and in the A/N classifications. Table S1. Demographic and clinical characteristics of the entire sample. Table S2. Associations of CSF sTREM2 with AD CSF core biomarkers including the biomarkers outliers. Table S3. Associations of CSF sTREM2 with AD CSF core biomarkers including subjects carrying a TREM2 rare variant. (DOCX 1992 kb)

CSF sTREM2 measurement. Figure S1. Effects of rare TREM2 variants on antibody affinities. Figure S2. CSF sTREM2 in the A/T and in the A/N classifications. Table S1. Demographic and clinical characteristics of the entire sample. Table S2. Associations of CSF sTREM2 with AD CSF core biomarkers including the biomarkers outliers. Table S3. Associations of CSF sTREM2 with AD CSF core biomarkers including subjects carrying a TREM2 rare variant. (DOCX 1992 kb)

CSF sTREM2 measurement. Figure S1. Effects of rare TREM2 variants on antibody affinities. Figure S2. CSF sTREM2 in the A/T and in the A/N classifications. Table S1. Demographic and clinical characteristics of the entire sample. Table S2. Associations of CSF sTREM2 with AD CSF core biomarkers including the biomarkers outliers. Table S3. Associations of CSF sTREM2 with AD CSF core biomarkers including subjects carrying a TREM2 rare variant. (DOCX 1992 kb)

La malaltia d’Alzheimer (MA) està precedida per una llarga etapa preclínica, en la qual es desenvolupa la patologia cerebral en absència de simptomatologia. La identificació acurada d’aquesta fase preclínica, i un millor coneixement de les seves vies fisiopatològiques, són claus per identificar estratègies preventives eficaces. L’objectiu d’aquesta tesi és estudiar la fase preclínica de l’Alzheimer utilitzant biomarcadors de fluid. En concret, hem estudiat biomarcadors en líquid cefaloraquidi i en sang per diverses vies fisiopatològiques relacionades amb la MA en participants cognitivament sans però amb un risc elevat de desenvolupar MA. Els resultats demostren que l’aproximació utilitzada per definir l’Alzheimer preclínic influencia les característiques dels participants classificats en aquest grup. A més, diversos processos fisiopatològics s’activen tant aviat com hi ha evidència d’alteracions en la proteïna amiloide-β. Finalment, els resultats també indiquen que és possible detectar l’Alzheimer preclínic amb nous biomarcadors en sang. En conclusió, els resultats d’aquesta tesi contribueixen a un millor coneixement de la fase preclínica de l’Alzheimer i donen suport a considerar els individus en aquesta fase per a estudis clínics dirigits a prevenir l’aparició dels símptomes. Alzheimer’s disease (AD) is preceded by a long preclinical phase in which there is detectable brain pathology but clinical symptoms are not yet present. Llittle is known about the pathophysiological pathways arising at this preclinical stage. An accurate identification of preclinical Alzheimer and a better understanding of its pathophysiological pathways are key to identify and design effective preventive strategies. The aim of this thesis is to characterize the preclinical stage of the Alzheimer’s continuum with fluid biomarkers for AD-related pathological processes. We studied CSF and blood biomarkers for AD-related pathways in cognitively unimpaired individuals at increased risk for AD. The results demonstrated that the approach used to define preclinical Alzheimer influences the features of individuals in this group. We also showed that multiple pathophysiological processes start as soon as there is evidence of amyloid-β dysregulation. Finally, we found that novel blood biomarkers can accurately detect preclinical Alzheimer. Taken together, our findings improve the understanding of the preclinical stage of the Alzheimer’s continuum and support the consideration of individuals within this early stage for clinical studies aimed at preventing the symptoms onset.